The human T-cell leukemia viruses, types 1 (HTLV-1) and 2 (HTLV-2), are etiologically associated with specific T-cell neoplasms in humans and transform T cells in vitro. The HTLV accessory gene, tax, likely serves an integral function in the process of HTLV- induced leukemogenesis and T-cell transformation. Tax is required in-trans for efficient replication of HTLV. It also regulates expression of several cellular genes in T cells. Consequently, tax has been postulated to induced T-cell leukemia via a mechanism in which it induces aberrant regulation of normal T-cell gene expression. The molecular and biochemical mechanism(s) by which Tax acts are unclear. Our longterm goal has been to determine how HTLV induces T-Cell transformation and leukemia, focusing on how HTLV Tax functions to dysregulate gene expression in T cells. Preliminary studies indicate: that Tax functions to regulate gene expression indirectly, through one or more transcription factors; that Tax operates on multiple classes of transcription factors; and that transformation of T cell by HTLV alters normal signal transduction pathway(s) mediating expression of certain host T-cell genes. Recently, we identified, isolated, and initiated characterization of TRC-1 [Tax-elements in the proviral long terminal repeat (LTR) and is likely involved in HTLV replication. This factor, which is overexpressed in HTLV-transformed T cells, but not in non-HTLV-infected cells, may play a role in HTLV pathogenesis. TRC-1 is heteromultimeric, containing polypeptides p21 and p40/43. Partial amino acid sequence analysis of p21 indicates that it is a novel protein. Immunologic and biochemical analyses of p40/43 suggest that it is composed of differentially phosphorylated forms of JunB or a JunB-related protein. The binding activity of TRC-1 is independent of Tax. The specific objectives of this proposal are to: 1. Clone and characterize the p21 and p40/43 components of TRC-1; 2. Study the regulation of TRC-1 expression, especially as it pertains to T cells; 3. Define functional domains in TRCp21 and TRCp40/43 via structure/function analyses; 4. Determine the role of protein phosphorylation in regulation of TRC-1 activity; 5. Define the physical and functional interactions between HTLV Tax and TRC-1 and 6. Investigate the role of TRC-1 in HTLV-transformed T-cell proliferation and gene expression. In that the only known target for HTLV-induced neoplasia in vivo is T cells, investigation of TRC-1 and the mechanism of its activation/response to the HTLV Tax protein will be insightful for our understanding of HTLV biology, as well as our perceptions regarding the role of TRC-1 and Tax in T-cell gene regulation and in HTLV-mediated leukemogenesis.